Neuroleptic medication is clearly effective in alleviating psychotic symptoms and reducing relapse rates in schizophrenia. However, some patients do not respond to such treatment and others respond equally well on placebo. Thus, neuroleptic treatment may be unwarranted for some types of schizophrenia. Since neuroleptic treatment is associated with deleterious and sometimes irreversible side effects, the delineation of subtypes not requiring medication has direct implications for clinical care. Our review of the literature also suggests that attention to treatment responsiveness may help to resolve the problem of genetic heterogeneity in schizophrenia. Hypotheses are derived from two alternative models of heterogeneity to predict clinical, familial and neuropsychological characteristics among treatment response subtypes. Three subtypes will be examined. Chronically psychotic, neuroleptic independent patients will be defined on the basis of a medical record history of unremitting psychotic symptoms and adequate neuroleptic bioavailability on their usual clinical dose. Neuroleptic dependent patients will be defined on the basis of a medical record history of remitting psychotic symptoms and the observation of clinical relapse during a six month trial of a 80% dose reduction. Episodically psychotic patients will have had a medical record history of remitting psychotic symptoms but will not have relapsed during dose reduction despite evidence of low neuroleptic bioavailability as measured by serum neuroleptic and serum prolactin levels. Before the dose reduction phase, all patients will be assessed with the Diagnostic Interview Schedule to verify a DSM-III diagnosis of schizophrenia, the Luria-Nebraska Neuropsychological Battery to assess neuropsychological functioning and psychosocial measures to assess the severity of the disorder and the presence of moderating factors. We expect the 60 subjects in each drug response group to have an average of 2.5 biological relatives available for interview. These 450 relatives will be assessed with the Diagnostic Interview Schedule and the Structured Interview for DSM-III Personality Disorders to determine psychiatric diagnoses of schizophrenia and schizophrenia related personality disorders. The assessment and diagnosis of relatives will be blind to the assessment and diagnosis of probands and vice-versa. All proband and relative assessments will be blind to drug response status. Data analyses will test predictions from Multifactorial Polygenic and Discrete Subtype models of genetic heterogeneity to develop rules for predicting treatment response and familial risk.